Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
Poly(ADP-ribose) polymerase 1 (PARP-1) is an abundant and ubiquitous nuclear enzyme. When active, it captures nicotinamide adenine dinucleotide (NAD) to assemble long and branching molecules of Poly(ADP-ribose) (pADPr), thereby modifying itself as well as surrounding proteins. Although DNA repair is commonly accepted as its main function, recent findings indicate that PARP-1 also participates in numerous nuclear processes, including transcription regulation and epigenetic bookmarking. PARP-1 tends to localize in promoter regions of genes involved in cell adhesion and cell-to-cell signaling, controlling their expression.
PARP-1 inhibitors have been shown to selectively eliminate several types of tumorigenic cells. In recent years, PARP-1 inhibitors became popular in clinical research on novel strategies of cancer treatment and, a number of PARP-1 inhibitors are currently undergoing clinical trials for treatment of genetically disposed mutant tumors. Unfortunately, a number of clinical studies reported setbacks in research on PARP-1-based anticancer therapies.
One of the factors that may limit the potency of PARP-1 inhibitors is the majority of currently available inhibitors were designed as NAD competitors (FIGS. 1A and 1B). NAD is abundant, ubiquitous, and is used by many other enzymes. Therefore, it is very difficult to completely eliminate NAD interaction with PARP-1 without drastically affecting other metabolic processes. Moreover, as classical PARP-1 inhibitors demonstrate substantial similarities to nucleotide analogues, they obstruct functions of enzymes which utilizing nucleotides as cofactors, such as kinases.
As PARP-1 remains a viable target in cancer therapy, there remains a need for PARP-1 inhibitors that do not affect other enzymes or other normal metabolic processes. Relatedly, there remains a need for PARP-1 inhibitors that diverge from the established model of aiming at the NAD-PARP-1 interaction.